Wednesday, September 13, 2006
Dialysis Unplugged
Will nano-engineered implants set kidney patients free?By Peter Fairley
Conventional dialysis, in which a patient’s blood is pumped through an external filter to drain out accumulating toxins, is far from ideal for the 1.4 million people with kidney disease worldwide whose lives depend on it. The common regimen of three half-day blood-cleansing sessions per week removes, on average, just 17 percent of the toxins that a healthy kidney would clear, so that only one-third of all dialysis patients survive more than five years of treatment.
Nanotechnology could offer an alternative, according to nephrologist William Fissell at the University of Michigan. He and colleagues are working on nano-pore membranes that could enable dialysis to be miniaturized into implantable devices that provide round-the-clock clearance of toxins, untethering dialysis patients from bulky pumps and clinics. “This is a fundamentally liberating technology,” says Fissell.
Fissell and colleague Shuvo Roy, a biomedical engineer at the Cleveland Clinic Foundation, claim to have solved half of the challenge: engineering nano-membranes that are efficient enough to support a compact, low-power implant. The team secured a patent for the concept earlier this year. However, engineering pores with the required selectivity–pores that drain away the worst toxins without robbing the body of critical proteins such as albumin, blood clotting factors, and antibodies–is proving to be tougher than expected.
As currently practiced, dialysis is a crude procedure. Patients are hooked up intravenously to a powerful pump that circulates their blood through a cartridge of porous plastic fibers. Fluids, dissolved toxins, and salts pass through the fibers and are discarded, while the proteins and blood cells caught in the sieve are supplemented with electrolyte before returning to the patient. The filter’s poor fluid dynamics are a function of their imprecision: filter manufacturing produces a wide range of pores, so to avoid having too many large pores, which would suck out valuable proteins, the fibers must be manufactured with a preponderance of very small pores. The machine’s pump makes up the difference, forcing blood through these inefficient sieves.
In contrast, Fissell and Roy etch pores into ultrathin wafers of silicon with lithographic precision. The result is a homogenous array of pores, each capable of flow rates several orders of magnitude higher than the average pore in a conventional filter. The pores mimic the exquisitely precise yet efficient diaphragms that filter blood in a human kidney, resembling a panel of Venetian blinds, says Fissell.
Current prototypes contain roughly 10,000 pores per square millimeter, according to Fissell. Next-generation membranes, now being engineered, will have more than 100,000 pores or slits per square millimeter and provide more than 10 times the flow. An implanted device carrying several hundred square centimeters of this next-generation membrane should, Fissell estimates, filter at least 30 milliliters of blood per minute at average blood pressures–about one-third of normal kidney function. The implant would be tucked under the skin; small fluid bags worn externally could receive the ultrafiltrate and supply replacement electrolytes.
Controlling what goes through the slits, however, remains a problem. While even the largest blood toxins easily slide through the membrane’s slits, experiments with prototypes suggest that the smallest of the valuable proteins, albumin, will also drain through. Dextran, a complex sugar used as a surrogate for albumin in filtration tests, flies right through the prototype pores, despite measuring roughly 40 nanometers in diameter, which is three to four times wider than the pores. Fissell thinks that the dextran, a long-chain molecule normally scrunched up like a wad of paper, stretches out when it encounters the slit pores and snakes through–something that a protein chain like albumin might also do.
Fissell’s team is testing whether the kidney sorts not only by size but also by generating electrical charges that repel protein chains, which are also charged. They’re modeling various chemical modifications to introduce charges on the surface of the silicon pores.
To make the system practical will require rendering the membranes biocompatible. Unmodified silicon strongly attracts proteins, and thus a silicon nano-pore membrane would rapidly clog if implanted in the body. Fissell’s colleague at the University of Michigan, David Humes, has initiated animal studies with the nano membranes to identify surface treatments or alternative membrane materials that will prevent clogging in implants.
Humes hopes to use the membranes to fashion a more sophisticated version of the implant that would contain living kidney cells–analogous to his “bioartificial” Renal Assist Device that’s currently in phase two clinical trials (see “Saving Lives with Living Machines,” July/August 2003). In an implantable version of the bio-artificial kidney, nano-pore membranes would protect the live kidney cells from immune cells and antibodies, which have thwarted most bio-artificial organ implants to date. The live kidney cells, in turn, would improve the function of the implant by reabsorbing and returning to the bloodstream some of the fluids and salts that pass through the nano-pore membrane. Eventually, bio-artificial implants that recover fluids and salts and divert the remaining ultrafiltrate to the bladder might even eliminate the need for external electrolyte and ultrafiltrate bags.
UCLA Medical School nephrologist Allen Nissenson, who has worked extensively to support the development of portable dialysis devices, says it remains to be seen if the University of Michigan researchers can squeeze their filtration systems into a package small and robust enough for implantation. But he says their goal to more precisely emulate the function of the kidney is right on–and a welcome alternative to the incremental improvements in more conventional technologies that have dominated dialysis developments for the past 20 years. Innovations that “more closely mimic the way natural kidneys function are really the cutting edge for the future of therapy,” he says.
Fissell’s 30 milliliters per minute of filtration would provide more than 30 percent of normal kidney function–a huge improvement, according to William Harmon, director of nephrology at Children’s Hospital in Boston. It’s an “important threshold,” he says, above which many symptoms of kidney disease would fade: “If you’re at 30 percent you’re doing quite well.”
Very interesting plans there and complex as it can be. They really need to iron our some challenges they’re facing! On the other hand, what I see here also the advantage of making our current portable dialysis machine like NxStage much smaller and lighter! I can see in my head the next generation NxStage System Two, weighing only 35lbs !! 
…and the generation after that might fit in your head, Gus ! :lol:
-Bear
I would love a lighter NxStage machine, but what would be realy cool. Would be a living filter and tubing that didn’t have that smell. Oh’ and the taste I get from the tubing when the machine starts, yukl that’s gotta be bad for you. I guess I couldn’t get the living filter, but what about reuse or something. That would be a nice addition to an all ready great machine…;
LSB
Oh yes, the lighter the better to get around… 
Btw, have you tried flushing the lines with an extra saline bag? That helps reducing the funky taste…
Btw, have you tried flushing the lines with an extra saline bag? That helps reducing the funky taste…
At what point in the tx. would flushing the lines with an extra saline bag be done? Would this be considered double priming and take another 18 minutes?
After setup is all done, you’d replace the old slaine bag with a new one then you’d flush the lines out…finally, you get on…its only about 3-5min…
Gus wrote:
After setup is all done, you’d replace the old slaine bag with a new one then you’d flush the lines out…finally, you get on…its only about 3-5min…
Ok thanks, I see. Has anyone figured out what the “funky taste” is and if it poses a health problem? Does doing a 2nd flush remove the plasticl taste everytime?
I could flush with an extra saline bag, but I would have to pay for it. They are very strick on what they will pay for, being that I am part of a study group. I am sure I could figure it out, but it would just be nice if NxStage would figure it out. So I wouldn’t have to use two saline bags. Just thought about it though, how would you flush the lines with saline? You would have to be able to remove the saline from the system. Is there some way of hooking the drain line up and using it to flush the lines with? I actualy don’t think this is possible with the NxStage machine. I may be wrong and if you could explain to me how that would be great…
Peace;
LSB
I am guessing if it is done anything like it’s done in-center, one would disconnect the venous line and discard in a bucket being very careful not to contaminate the line which is hooked up to patient.
For safety I cannot give detailed instructions, you’ll need to consult with NxStage or your clinic. However, you have the idea… 
Gus wrote:
After setup is all done, you’d replace the old slaine bag with a new one then you’d flush the lines out…
After prime is done there should be about half a bag left. So if the first bag is taken off and replaced with a new bag, how much of the new bag do you flush with?